Asthma therapy: fixed combinations administered by a fixed combination inhaler are not superior to the same drugs administered by separate inhalers

The Institute for Quality and Efficiency in Health Care (IQWiG) assessed whether patients benefit more from novel fixed combinations administered by a fixed combination inhaler than from the same drugs administered by separate inhalers (or vice versa). Weighing the benefits and harms of both interventions, the Institute's final report (published on the 5 June 2007) came to the conclusion that there is no scientific evidence of a superiority of one of the two forms of administration. In fact, if the same inhaling systems are used, the studies currently available show similar results for both forms of administration.

Formoterol/budesonide and salmeterol/fluticasone were evaluated

IQWiG assessed the benefit of the interventions for patients by assessing, among other things, whether there was a reduction in the severity of asthma symptoms, exacerbation rates, hospital admissions, outpatient visits, and adverse events. Other outcomes defined in the report were health-related quality of life, physical capacity, as well as restrictions in activities of daily living.

The report compared formoterol/budesonide (tradename in Germany: Symbicort) or salmeterol/fluticasone (tradenames in Germany: Viani, Atmadisc), administered by a fixed combination inhaler, with the same drugs administered by separate inhalers in patients with asthma. No superiority of one form of administration over the other was shown.

In addition, both fixed combinations were compared with each other (formoterol/budesonide vs. salmeterol/fluticasone). No superiority of one fixed combination over the other was shown.

Changed approval status in asthma therapy will be evaluated in a follow-up project

The fixed combination of formoterol/beclometasonedipropionate (tradenames in Germany: Foster, Inuvair) was not evaluated, as it had not been approved in Germany when IQWiG started its evaluation. (In the meantime, approval has been given.) The same applies to the fixed combination of formoterol/budesonide as reliever therapy (tradename in Germany: Symbicort SMART), which was also not considered in the present evaluation. Both therapies will therefore be evaluated in a follow-up project.

Only few data available in children

Eleven studies were included in the evaluation. Overall, the number and quality of available studies were classified as sufficient to make reliable conclusions for adolescents and adults. The situation for children is different: only one study was available comparing salmeterol/fluticasone administered by a fixed combination inhaler with salmeterol and fluticasone administered by separate inhalers. No study comparing the two forms of administration of formoterol and budesonide was identified.

No studies assessing adherence to therapy available

One argument supporting the use of fixed combinations is the assumption that they improve patients' adherence to therapy. However, IQWiG did not find data that confirm this assumption, as studies with an appropriate design were lacking. Moreover, adherence to therapy per se does not yet represent an additional benefit. This only arises when improved adherence also leads to better results concerning patient-relevant outcomes such as, for example, breathlessness.

IQWiG disagrees with claims that evidence of better therapy success as a result of increased adherence to therapy cannot be produced in randomised controlled trials (RCTs), because patients in this setting show stricter adherence to therapy in any case. In the opinion of IQWiG, RCTs (where patients are allocated by chance to one of the groups to be compared) can realistically represent everyday treatment practice. The precondition for this is, among other things, that patients do not need to fulfil specific requirements affecting adherence that do not exist in their everyday life. This includes, for example, writing down exactly when they take which medications.

Procedure of report production

The preliminary report was published by IQWiG on its website on 18 January 2007. Interested persons and parties were asked to submit comments. Open issues pertaining to a total of 19 submitted comments were discussed with the authors of the comments in a scientific debate held in Cologne on 6 March 2007. The meeting minutes of this oral debate, as well as the comments themselves, are documented in the appendix of the final report. The arguments presented in the comments are discussed in detail in the report, in particular in the discussion section (pp. 125-137). The final report was completed before the GKV-WSG, the "Act to promote competition of the statutory health insurance”, became operative on 1 April 2007, and was forwarded to the contracting agency, the Federal Joint Committee.

Preliminary report plan (protocol) of the follow-up project is open for comments

On 6 March 2007, the German Federal Joint Committee commissioned IQWiG to perform a follow-up project. IQWiG is also to evaluate newly approved novel fixed combinations or fixed combinations that can be used for broader indications. The preliminary report plan for this evaluation was published, together with the first final report, on 5 June 2007 on the IQWiG website. Interested institutions, as well as other parties and persons, are invited to submit comments by 3 July 2007 on the project-specific methodology outlined in the report plan. The results of both projects will subsequently be merged by IQWiG and will then serve the Federal Joint Committee as a basis for decision-making.

Contact: info@iqwig.de